p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
Authors
- Peter D. Adams (ORCID: https://orcid.org/0000-0002-0684-1770)
- João F. Passos (ORCID: https://orcid.org/0000-0001-8765-1890)
- Aaron Havas (ORCID: https://orcid.org/0000-0003-4291-8015)
- A. Korotkov (ORCID: https://orcid.org/0000-0002-8313-6282)
- Xue Lei (ORCID: https://orcid.org/0000-0001-9647-3782)
- Tianhui Liu (ORCID: https://orcid.org/0000-0001-6789-3016)
- Armin Gandhi (ORCID: https://orcid.org/0000-0002-8246-4663)
- Yoav Altman (ORCID: https://orcid.org/0000-0001-6075-1111)
- Andrew Davis
- Nirmalya Dasgupta (ORCID: https://orcid.org/0000-0002-0289-5712)
- Zhixun Dou (ORCID: https://orcid.org/0000-0002-3069-3907)
- Chongyi Chen
- Seung‐Hwa Woo (ORCID: https://orcid.org/0000-0002-9336-4457)
- Marcos G. Teneche (ORCID: https://orcid.org/0000-0003-4785-7987)
- Stella Victorelli (ORCID: https://orcid.org/0000-0001-5573-8019)
- Vera Gorbunova (ORCID: https://orcid.org/0000-0001-8979-0333)
- Rebecca A. Porritt (ORCID: https://orcid.org/0000-0002-0973-5092)
- Zichen Gao
- Carolina Cano Macip
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Anthony B. Lagnado (ORCID: https://orcid.org/0000-0002-9380-5179)
- Andrei Seluanov (ORCID: https://orcid.org/0000-0003-3400-538X)
- Karl N. Miller (ORCID: https://orcid.org/0000-0002-6076-3136)
- Susan M. Kaech (ORCID: https://orcid.org/0000-0003-1674-1420)
- Guillermina Ávila García (ORCID: https://orcid.org/0000-0001-5229-3384)
- Shreeya Patel (ORCID: https://orcid.org/0000-0003-2480-7274)
- Xiao Tian (ORCID: https://orcid.org/0000-0001-5300-3596)
- Hannah R. Pierce-Hoffman
- Sha Li (ORCID: https://orcid.org/0000-0002-1006-1785)
- Jun Lyu
- Brightany Li
- Michael A. LaPorta (ORCID: https://orcid.org/0009-0001-0461-5614)
- Adarsh Rajesh (ORCID: https://orcid.org/0009-0003-4326-7442)
- Erik Hultenius
Institutions
- National Institutes of Health (US)
- Salk Institute for Biological Studies (US)
- La Jolla Institute for Immunology (US)
- Mayo Clinic (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- California Institute for Regenerative Medicine (US)
- Discovery Institute (US)
- Harvard University Press (US)
- Mayo Clinic in Arizona (US)
- Center for Neuroscience and Regenerative Medicine (US)
- National Cancer Institute (US)
- Taipei Institute of Pathology (TW)
- Mayo Clinic in Florida (US)
- La Jolla Institute For Molecular Medicine (US)
- Harvard Stem Cell Institute (US)
- University of Rochester (US)
- Technical University of Munich (DE)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1038/s41467-025-57229-3
- Citations
- 23
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 26.78